Combined genome-wide association studies of cannabis dependence and personality traits
BACKGROUND: Cannabis dependence (CaD) and component behaviors of personality are highly heritable, but the genetic basis of these traits is poorly understood. Since several attributes of personality (e.g. neuroticism) are strongly correlated with cannabis use, we hypothesized that specific combined genetic underpinnings contribute to both CaD and to certain aspects of personality. METHODS: Personality was quantified with the Revised NEO Personality Inventory that asked questions from the five personality domains. Personality information was acquired from 1931 African Americans (AAs) and 1517 European Americans (EAs). CaD was measured as a summation of the seven binary DSM-IV diagnosis symptoms within a separate set of 1311 AAs and 2752 EAs in the NIH-funded "Study of Addiction: Genetics and Environment" (SAGE). Genome-wide association studies (GWAS) were performed after filtering out single-nucleotide polymorphisms (SNPs) with low minor allele frequency (MAF) and poor imputation quality. The personality trait was used as the outcome in the primary data set while CaD was used in the SAGE data set. Meta-analysis was used to combine the results for both traits within and across ethnic groups. Additionally, while honing in on the personality / CaD comparison, the analysis further investigated component facets of the NEO domain most strongly correlated to CaD. RESULTS: Genome-wide significant (GWS) results were obtained for EAs from the bivariate analysis of CaD paired with the extraversion domain (rs12534830, p=1.73E-08) near SEMA3D and paired with the vulnerability to stress facet, which is a component of the neuroticism domain (rs76021834, p=1.58E-08) within POR. GWS association was also observed with the vulnerability to stress facet considered as a single outcome in a SNP within the solute carrier gene SLC35F3 (rs12047995, p=3.55E-08) in the combined sample of AAs and EAs. DISCUSSION: Notable associations with both CaD and several personality traits include SNPs from multiple semaphorin genes whose protein products are axonal growth cone guidance molecules. These SNPs were either within or proximal to SEMA3A, SEMA3D, SEMA6A, or SEMA6D, which have links to schizophrenia, as discussed in many other studies. Further investigation in independent data sets is warranted to confirm the validity of these findings.